Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma

Introduction:The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.Materials and Methods:We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.Results:Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.Discussion:Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data

Chimpanzees demonstrate individual differences in social information use

Studies of transmission biases in social learning have greatly informed our understanding of how behaviour patterns may diffuse through animal populations, yet within-species inter-individual variation in social information use has received little attention and remains poorly understood. We have addressed this question by examining individual performances across multiple experiments with the same population of primates. We compiled a dataset spanning 16 social learning studies (26 experimental conditions) carried out at the same study site over a 12-year period, incorporating a total of 167 chimpanzees. We applied a binary scoring system to code each participant’s performance in each study according to whether they demonstrated evidence of using social information from conspecifics to solve the experimental task or not (Social Information Score—‘SIS’). Bayesian binomial mixed effects models were then used to estimate the extent to which individual differences influenced SIS, together with any effects of sex, rearing history, age, prior involvement in research and task type on SIS. An estimate of repeatability found that approximately half of the variance in SIS was accounted for by individual identity, indicating that individual differences play a critical role in the social learning behaviour of chimpanzees. According to the model that best fit the data, females were, depending on their rearing history, 15–24% more likely to use social information to solve experimental tasks than males. However, there was no strong evidence of an effect of age or research experience, and pedigree records indicated that SIS was not a strongly heritable trait. Our study offers a novel, transferable method for the study of individual differences in social learning

Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation

BACKGROUND: Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT. METHODS AND FINDINGS: We genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5-35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss. CONCLUSION: Our data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings

On the Anticorrelation Between Galaxy Light Concentration and X-ray-to-Optical Flux Ratio

Active Galactic Nuclei (AGN) play an important role in many aspects of the modern cosmology, and of particular interest is the issue of the interplay between AGN and their host galaxy. Using X-ray and optical data sets, we have explored the properties of a large sample of AGNs in the Subaru/XMM-Newton Deep Survey (SXDS) field, and studied their evolution in relation with the evolution of their host galaxy. We present here an anticorrelation between X-ray-to-optical flux ratio (X/O) and galaxy light concentration (C), which has been found for the first time and might suggest that early type galaxies, having poor matter supply to feed the AGN activity, have lower Eddington rates than those of late type galaxies.Comment: 9 pages, 3 figures, accepted for publication in ApJ Letter

Pregnancy outcomes related to the treatment of sarcomas with anthracyclines and/or ifosfamide during pregnancy

BACKGROUND: Sarcomas are rare diagnoses but are seen with relative frequency in adolescents and young adults and thus can present in pregnancy. We sought to study the administration of anthracyclines and/or ifosfamide in pregnancy-associated sarcomas. PATIENTS AND METHODS: We conducted a multi-institutional retrospective study, identifying sarcoma patients who received anthracyclines and/or ifosfamide during pregnancy. Chart review identified variables related to demographics, cancer diagnosis, therapies, and outcome of the patient and fetus. Wilcoxon rank-sum test compared two independent samples. RESULTS: We identified 13 patients at seven institutions with sarcoma who received anthracyclines and/or ifosfamide during pregnancy, including four bone sarcomas and nine soft tissue sarcomas diagnosed at a mean gestational age of 16.7 ± 5.9 weeks. Only nine patients had live births (9/13, 69.2%), with mean gestational age of 30.8 ± 3.8 weeks at delivery. The four patients with pregnancy loss all received both doxorubicin and ifosfamide, with chemotherapy initiated at 15.5 weeks as compared with 21.3 weeks for those patients with live births (p = 0.016). CONCLUSION: In this multi-institutional study of sarcoma chemotherapy regimens administered during pregnancy, we found a high rate of fetal demise that was seen only in patients receiving both doxorubicin and ifosfamide and statistically more likely with chemotherapy initiation earlier in the second trimester. While limited by a small sample size, our study represents the largest study of sarcoma patients that received anthracyclines and/or ifosfamide in pregnancy thus far reported and supports development of an international registry to study concerns raised by our study

A Mechanism-Based Explanation of the Institutionalization of Semantic Technologies in the Financial Industry

Part 3: Creating Value through ApplicationsInternational audienceThis paper explains how the financial industry is solving its data, risk management, and associated vocabulary problems using semantic technologies. The paper is the first to examine this phenomenon and to identify the social and institutional mechanisms being applied to socially construct a standard common vocabulary using ontology-based models. This standardized ontology-based common vocabulary will underpin the design of next generation of semantically-enabled information systems (IS) for the financial industry. The mechanisms that are helping institutionalize this common vocabulary are identified using a longitudinal case study, whose embedded units of analysis focus on central agents of change—the Enterprise Data Management Council and the Object Management Group. All this has important implications for society, as it is intended that semantically-enabled IS will, for example, provide stakeholders, such as regulators, with better transparency over systemic risks to national and international financial systems, thereby mitigating or avoiding future financial crises

An objective assessment of the impact of tendon retraction on sleep efficiency in patients with full-thickness rotator cuff tears: a prospective cohort study

Background Sleep quality, quantity, and efficiency have all been demonstrated to be adversely affected by rotator cuff pathology. Previous measures of assessing the impact of rotator cuff pathology on sleep have been largely subjective in nature. The aim of the present study was to use an objective measure of sleep quality and to compare these findings to the patients’ Patte stage. Methods Patients with full-thickness rotator cuff tears at a single institution were prospectively enrolled between 2018 and 2020. Waist-worn accelerometers were provided for the patients to use each night for 14 days. Sleep efficiency was calculated using the ratio of the time spent sleeping to the total amount of time that was spent in bed. Retraction of the rotator cuff tear was classified using the Patte staging system. Results This study included 36 patients: 18 with Patte stage 1 disease, 14 with Patte stage 2 disease, and 4 patients with Patte stage 3 disease. During the study, 25 participants wore the monitor on multiple nights, and ultimately their data was used for the analysis. No difference in the median sleep efficiency was appreciated amongst these groups (P>0.1), with each cohort of patients demonstrating a generally high sleep efficiency. Conclusions The severity of retraction of the rotator cuff tear did not appear to correlate with changes in sleep efficiency for patients (P>0.1). These findings can better inform providers on how to counsel their patients who present with complaints of poor sleep in the setting of full-thickness rotator cuff tears. Level of evidenceLevel II

Preparing tomorrow's teachers to use technology (PT3) at Boston University through faculty development: assessment of three years of the project

The Boston University PT3 grant project proposed first to train faculty to use technology and then to sustain the gained expertise in a curriculum development project. Education faculty gains in integrating technology into their teaching and their modeling of that use were clearly demonstrated in phase one of the project (the initial two years of the project). In phase two (the third year), faculty were challenged to produce innovative, interdisciplinary curriculum development projects investigating judgment in their discipline. Prototypes of the Judgment Curriculum produced in phase two of the project demonstrate an intersection of technology competence and innovative, question‐driven instruction. Preliminary data show strong gains in faculty use of technology in their teaching and in faculty requirements that their students use technology in education coursework. However, continued development of the Judgment Curriculum lessons remains a challenge

AGN-Host Galaxy Connection: Morphology and Colours of X-ray Selected AGN at z < 2

The connection between AGN and their host galaxies has been widely studied over recent years, showing it to be of great importance for providing answers to some fundamental questions related with AGN fueling mechanisms, their formation and evolution. Using X-ray and one of the deepest broad-band optical data sets, we studied morphology and colours in relationship with X-ray properties for sources at redshifts z < 2.0, using a sample of 262 AGN in the Subaru/XMM-Newton Deep Survey (SXDS). Morphological classification was obtained using the galSVM code, one of the new methods useful especially when dealing with high-redshift sources and low-resolution data. Colour-magnitude diagrams were studied in relationship with redshift, morphology, X-ray obscuration, and X-ray-to-optical flux ratio. Finally, the significance of different regions was analysed on colour-magnitude diagrams, relating the observed properties of AGN populations with some models of their formation and evolution.Comment: 24 pages, 19 figures, accepted for publication in Astronomy&Astrophysic